Hypoxia modulates lipopolysaccharide induced TNF-α expression in murine macrophages

Liu, Feng Qin; Liu, Yan; Lui, Vincent Chi Hang; Lamb, Jonathan R.; Tam, Paul K. H.; Chen, Yan

doi:10.1016/j.yexcr.2008.01.007

Cited by 42 publications

(33 citation statements)

References 42 publications

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“…The inhibitor concentrations were decided according to previous studies in RAW264.7 cells (42)(43)(44). In these experiments, RAW264.7 cells were incubated with wortmannin (PI3K inhibitor), SB203580 (p38 inhibitor), SP600125 (JNK inhibitor), or PD098059 (ERK inhibitor) 1 h before hypoxic stimulation, and then the expression of GILZ was detected by Western blot.…”

Section: Erk Activity Is Involved In the Induction Of Gilz By Hypoxiamentioning

confidence: 99%

Upregulations of Glucocorticoid-Induced Leucine Zipper by Hypoxia and Glucocorticoid Inhibit Proinflammatory Cytokines under Hypoxic Conditions in Macrophages

Wang

Song

et al. 2012

The Journal of Immunology

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Hypoxia and inflammation often develop concurrently in numerous diseases, and the influence of hypoxia on natural evolution of inflammatory responses is widely accepted. Glucocorticoid-induced leucine zipper (GILZ) is thought to be an important mediator of anti-inflammatory and immune-suppressive actions of glucocorticoid (GC). However, whether GILZ is involved in hypoxic response is still unclear. In this study, we investigated the effects of hypoxic exposure and/or the administration of dexamethasone (Dex), a synthetic GC on GILZ expression both in vitro and in vivo, and further explored the relationship between GILZ and proinflammatory cytokines IL-1β, IL-6, and TNF-α under normoxic and hypoxic conditions. We found that hypoxia not only remarkably upregulated the expression of GILZ, but also significantly enhanced Dex-induced expression of GILZ in macrophages and the spleen of rats. ERK activity is found involved in the upregulation of GILZ induced by hypoxia. Inhibiting the expression of GILZ in RAW264.7 cells using specific GILZ small interfering RNA led to a significant increase in mRNA production and protein secretion of IL-1β and IL-6 in hypoxia and abrogated the inhibitory effect of Dex on expression of IL-1β and IL-6 in hypoxia. We also found that adrenal hormones played pivotal roles in upregulation of GILZ expression in vivo. Altogether, data presented in this study suggest that GILZ has an important role not only in adjusting adaptive responses to hypoxia by negatively regulating the activation of macrophages and the expression of proinflammatory cytokines, but also in mediating the anti-inflammatory action of GC under hypoxic conditions.

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Section: Erk Activity Is Involved In the Induction Of Gilz By Hypoxiamentioning

confidence: 99%

Upregulations of Glucocorticoid-Induced Leucine Zipper by Hypoxia and Glucocorticoid Inhibit Proinflammatory Cytokines under Hypoxic Conditions in Macrophages

Wang

Song

et al. 2012

The Journal of Immunology

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“…RelA and HIF-1a can be induced by LPS (9,10). To further study whether the altered expression of RelA and HIF-1a in Mclk1 +/2 mutants was likely to affect their immune function, we measured the levels of the two proteins in the livers of animals treated with a low dose of LPS (0.01 mg/kg) (Fig.…”

Section: Increased Basal and Lps-induced Hif-1a Expression In Livermentioning

confidence: 99%

“…We tested whether mutant macrophages were activated, with the typical increased antibacterial and inflammatory effector functions, as a result of the increased expression of HIF-1 and NF-kB (10,12,24,25). We used peritoneal macrophages cultured overnight to measure Tnfa mRNA expression by quantitative RT-PCR (Fig.…”

Section: Increased Classic Activation Of Macrophagesmentioning

confidence: 99%

“…To verify the causal links suggested by the analysis of the phenotype of Mclk1 +/2 mice, we used the RAW264.7 mouse macrophage-like cell line, which is a model for the study of macrophages, HIF-1a, and mitochondria (10,(31)(32)(33)(34)(35). The levels of nuclear HIF-1a were significantly increased upon siRNA knockdown of Mclk1 (Figs.…”

Section: Reduction Of Mclk1 Expression In Raw2647 Cells Increases Numentioning

confidence: 99%

“…Macrophages and other immune effector cells play important roles at these sites where they respond to the local hypoxia by upregulating HIF-1a; however, the upregulation of HIF-1a can also be triggered by stimuli other than hypoxia, such as cytokines (in T cells) (8) and LPS (in macrophages) (9). HIF-1, in turn (10), stimulates the expression of genes that are important for the effector function of macrophages (11,12). Recently, it was found that the transcriptional regulator NF-kB is one of the main links between innate immunity and the hypoxic response through its transcriptional control of Hif1a expression (13,14).…”

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confidence: 99%

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Elevated Mitochondrial Reactive Oxygen Species Generation Affects the Immune Response via Hypoxia-Inducible Factor-1α in Long-Lived Mclk1+/− Mouse Mutants

Wang¹,

Malo

Hekimi³

2009

The Journal of Immunology

115

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Mitochondrial reactive oxygen species (ROS) are believed to stabilize hypoxia-inducible factor (HIF)-1α, a transcriptional regulator of the immune response. Mclk1 encodes a mitochondrial protein that is necessary for ubiquinone biosynthesis. Heterozygote Mclk1+/− mutant mice are long-lived despite increased mitochondrial ROS and decreased energy metabolism. In this study, Mclk1+/− mutant mice in the C57BL/6J background displayed increased basal and induced expression of HIF-1α in liver and macrophages in association with elevated expression of inflammatory cytokines, in particular TNF-α. Mutant macrophages showed increased classical and decreased alternative activation, and mutant mice were hypersensitive to LPS. Consistent with these observations in vivo, knock-down of Mclk1 in murine RAW264.7 macrophage-like cells induced increased mitochondrial ROS as well as elevated expression of HIF-1α and secretion of TNF-α. We used an antioxidant peptide targeted to mitochondria to show that altered ROS metabolism is necessary for the enhanced expression of HIF-1α, which, in turn, is necessary for increased TNF-α secretion. These findings provide in vivo evidence for the action of mitochondrial ROS on HIF-1α activity and demonstrate that changes in mitochondrial function within physiologically tolerable limits modulate the immune response. Our results further suggest that altered immune function through a limited increase in HIF-1α expression can positively impact animal longevity.

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Drug Transporters in Health and Disease

Bennani‐Baïti

Noe

2009

Transporters as Drug Carriers

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Hypoxia modulates lipopolysaccharide induced TNF-α expression in murine macrophages

Cited by 42 publications

References 42 publications

Upregulations of Glucocorticoid-Induced Leucine Zipper by Hypoxia and Glucocorticoid Inhibit Proinflammatory Cytokines under Hypoxic Conditions in Macrophages

Upregulations of Glucocorticoid-Induced Leucine Zipper by Hypoxia and Glucocorticoid Inhibit Proinflammatory Cytokines under Hypoxic Conditions in Macrophages

Elevated Mitochondrial Reactive Oxygen Species Generation Affects the Immune Response via Hypoxia-Inducible Factor-1α in Long-Lived Mclk1+/− Mouse Mutants

Drug Transporters in Health and Disease

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